Montelukast sodium, also known as R-(E))-1-(((1-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid sodium salt, is represented by the structural Formula I:

Montelukast sodium is a leukotriene antagonist and inhibits the synthesis of leukotriene biosynthesis. It is useful as an antiasthmatic, anti-allergic, anti-inflammatory and cytoprotective agent and hence useful in the treatment of angina, cerebral spasm, glomerular nephritis, hepatic, end toxemia, uveitis and allograft rejection. Montelukast sodium is currently indicated for the treatment of asthma and allergic rhinitis.
Montelukast sodium, formulated as 10.4 mg montelukast sodium tablets, 4.2 or 5.2 mg montelukast sodium chewable tablets or 4.2 mg montelukast sodium oral granules packet, is typically given once daily to the patients for the treatment of asthma and seasonal allergic rhinitis. Montelukast sodium is marketed in the United States and other countries by Merck & Co., Inc. under the trade name Singulair®.
EP Patent No. 0480717 (“the '717 patent”) discloses montelukast sodium along with other related compounds and the methods for their preparation. The reported method of synthesis proceeds through corresponding methyl ester namely, and involves coupling methyl 1-(mercaptomethly)cyclopropane acetate with a tetrahydropyran (THP) protected mesylate compound. The methyl ester and the THP group are hydrolyzed to free acid and the later converted directly to montelukast sodium salt. The process is not suitable for large-scale production because it involves multiple steps such as series of protection and deprotection of intermediates and requires tedious chromatographic purification of the methyl ester intermediate and of the final product, which in turn result to an increase in the manufacturing cycle time and a decrease in the product yield. The process disclosed in the '717 patent is schematically represented as follows:

U.S. Pat. No. 5,614,632 (“the '632 patent”) discloses a process for the preparation of montelukast sodium and its process intermediates. The process involves reaction of 2-(2-(3(S)-(3-(2(7-chloro-2-quinolinyl)-ethenyl)phenyl)-3-hydroxypropyl)phenyl)-2-propanol (diol compound) with methane sulfonyl chloride in toluene and acetonitrile at temperature −35° C. and isolating the corresponding mesylate compound as crystalline compound by filtration and slurry wash with n-hexane followed by drying under nitrogen atmosphere. The crystalline mesylate compound obtained was condensation with 1-(mercaptomethyl)cyclopropaneacetic acid in presence of butyl lithium to yield montelukast acid, which is isolated as montelukast amine salt such as dicyclohexylamine salt and followed by the amine salt is converted in to crystalline montelukast sodium. It is mentioned by the inventors of the '632 patent that the crystalline montelukast dicyclohexylamine salt offers an efficient method for the purification of montelukast, which circumvents the need to use chromatographic purification. However, the '632 patent use multiple solvents for example use of toluene, acetonitrile and hexane during the preparation and isolation of mesylate compound, resulting an increase in the manufacturing cost.
Further, the crystalline mesylate compound used in the '632 patent is very unstable under normal atmospheric conditions and throughout the reaction to produce the mesylate compound must be performed at a low temperature of about −30° C. and the product is required to store at extremely sensitive conditions such as store at about −20° C. under nitrogen atmosphere; thus the process is not viable for large scale production of montelukast sodium.
The process disclosed in the '632 patent is schematically represented as follows:

U.S. Pat. No. 7,547,787 (“the '787 patent”) discloses a process for the preparation of montelukast sodium by reaction of montelukast diol compound with methane sulfonyl chloride in presence of diisopropylamine in tetrahydrofuran to obtain mesylate compound, which is in solution further directly reacted with 1-(mercaptomethyl)cyclopropane acetic acid methyl ester in a co-solvent such as dimethyl formamide, acetonitrile, N-methyl pyrrolilidone or dimethyl acetamide in presence of a base such as 47% sodium hydroxide solution, followed by hydrolysis of the resulting product to obtain montelukast sodium.
The '787 patent involves use of alkyl esters of 1-(mercaptomethyl)cyclopropane acetic acid, which adds an extra synthetic steps to the total synthesis of montelukast sodium such as esterification of the corresponding acid compound and hydrolysis of the esters, resulting in a process that is expensive in large scale production of montelukast sodium.
Moreover, the '787 patent teaches that the purity and yield of the montelukast sodium produced by the above method are 91% and 50% respectively. Extensive purification procedures are required in order to obtain the necessary quality of the end product and results low product thereby making the process quite expensive.
PCT Publication No. 2009/048236 (“the '236 publication”) discloses a process for the preparation of montelukast sodium by reaction of mesylate compound with bis-alkali metal salt 1-(mercaptomethyl)cyclopropane acetic acid in a solvent mixture of ionic liquid and dimethyl sulfoxide (DMSO) to obtain montelukast free acid as solid compound, which is further converted to its sodium salt. The '236 publication process has certain disadvantages such as use of ionic liquids and involves additional process step of isolation of montelukast free acid in solid form, which in turn result to an increase in the manufacturing cost.
PCT Publication No. 2009/138993 (“the '993 publication”) discloses a process to prepare montelukast sodium through use of phosphoric acid ester in place of unstable methane sulfonyl group of diol compound, which is reacted with alkyl ester of 1-(mercaptomethyl)cyclopropane acetic acid.
U.S. Pat. No. 8,178,680 (“the '680 patent”) discloses a process to prepare montelukast sodium by reaction of mesylate compound with 1-(mercaptomethyl)cyclopropane acetic acid in dimethyl sulfoxide in presence of a base such as sodium methoxide solution in methanol, followed by hydrolysis of the resulting product with water, basification with sodium hydroxide and then repeated solvent washings and extractions using toluene and ethyl acetate finally isolating the montelukast as an amine salt, and further conversion it into montelukast sodium.
The '680 patent involves tedious workup procedures such as solvent washings and extractions to isolate the required product and thus results in excess time cycle, which in turn rendering the process quite expensive.
Processes for the preparation of montelukast and/or its salts by using solid montelukast free acid are disclosed in various literatures for example WO 2004/108679, US2005/107612, WO 2005/74935, US 2005/107426, WO 2009/117381. Isolation of solid montelukast free acid in the preparation of montelukast sodium involves additional process steps such as filtration, drying and storage etc requires more labor and more operational occupancy, which in turn result to an increase in the manufacturing cost, particularly on large scale production of montelukast sodium.
The processes for the production of montelukast and/or its salts by using different amine salts were discussed for example in US 2005/107612, US 2006/004204, WO 2004/108679, WO 2006/008751, WO 2006/043846, WO 2007/004237, WO 207/069261, WO 2007/072114, WO 2007/088545, WO 2007/96875, WO 2007/96889, WO 2007/107297, WO 2007/116240, WO 2008/001213, WO 2008/009970, WO 2008/015703, WO 2008/017669, WO 2008/023044, WO 2008/032099, WO 2008/058118, WO 2008/062478, WO 2008/87628, WO 2008/126075, WO 2008/136693, WO 2009/06861, WO 2009/027990, WO 2009/052625, WO 2009/113087, WO 2009/117381, WO 2009/053424, WO 2009/098271, WO 2010/036048, WO 2010/064257, WO 2011/004298, WO 2011/076237, WO 2012/015255.
Our U.S. Pat. No. 8,207,343 discloses process for the preparation of montelukast sodium through use of 1-methyl-3-phenylpropyl amine salt of montelukast.
Although many processes have been described in the art for the preparation of montelukast and its salt thereof, there still remains a need for a process for manufacturing montelukast and their salts, which has minimal steps that avoids additional synthetic steps as described above on one hand and avoiding the use of chromatographic purification and hazardous reagents, improves the yield and quality of montelukast sodium.